A NCA analysis of approval documents Paul AF Jansen, geriatrician, - - PowerPoint PPT Presentation

A NCA analysis of approval documents

Paul AF Jansen, geriatrician, clinical pharmacologist

Dep Geriatrics and Ephor, UMC Utrecht, The Netherlands 23 March 2012

Pre-authorization studies and the users of medicines

Number of prescriptions in 2009 in the Netherlands

Benefit/risk is changing

• Evidence for benefit of

several medicines

• Time until benefit is shorter

compared to younger adults

• Safety is a problem because
• f changes in PK/PD
• Nerve system damage is

important

• Decrease in kidney function
• Decreased balance
• Decreased thirst etc.

The consequences: HARM frail patients are at risk to be admitted to hospital because of ADR

• Cognitive disturbance (HR 11,9; 3,9-36,3)
• Polymorbidity > 5 (HR 8,7; 3,1-24,1)
• decreased kidney function (HR 3,1; 1,9-

5,2)

• not living independently (HR 3,0;1,4-6,5)
• Polypharmacy (>5 HR 2,7; 1,8-3,9)
• Adherence problems (HR 2,3; 1,4-3,8)

Leendertse et al. Arch Int Med 2008;168: 1890-6

Is it true that older patients are not studied?

• Which information is available in

the SmPC for appropriate prescribing in older persons?

• Which information is available in

the EPAR for appropriate prescribing in older persons?

• What is the compliance with the

almost 20 year old ICH E7 guideline?

Erna Beers Prof Bert Leufkens Prof Toine Egberts Dr Paul Jansen www.ephor.eu

Methods

• All non-generic products with a European

centralised marketing authorisation between 2008 and 2011 with complete dossiers, indicated for diseases in older individuals

• The ICH E7 guideline was summarised in 19 items

19 items of the ICH E7

• Nature of the studied population ( 4 items)
• Inclusion >65 and >75 years
• Exclusion based on age
• Exclusions based on common co-morbidity
• Clinical experience in older patients (4 items)
• Number >65 years
• Age-related differences for efficacy, dose-response

and adverse events

• Pharmacokinetic studies (8 items)
• Drug-drug interaction studies (3 items)

Subdivision of available and missing information

Results

• 53 medicinal products
• Neoplasms: 12 (23%)
• Musculoskeletal system/connective tissue: 10 (19%)
• Circulatory system: 8 (15%)
• Endocrine, nutritional and metabolic diseases: 5 (9%)
• Infectious diseases: 5 (9%)
• Others: 13 (25%)

Available, positive information

Available, positive information per category

Non-available information that should have been positive

Non-available information that should have been positive per category

Conclusions

• Information on older persons, according to the ICH

E7 is relatively high available in the EPARs

• However it is often not present in the SmPC
• Especially information on common co-morbidities,
• n age-related differences in efficacy and kind of PK

study in older persons are lacking

Discussion: is the ICH E7 information what prescribers want?

• Delphi study on the Information of Medicine

appropriateness in the Elderly (DIME)

• Regulators found several items less important

compared to geriatricians/other experts:

• The convenience of use for older persons (dosage

form and packaging)

• The extent of renal clearance of the active

substances in old persons

• No exclusion based on concomitant medical

conditions common in old persons

What was left out

• f the final Dime?
• No exclusion based on concomitant medical conditions

common in old persons

• A single-dose pharmacokinetic study in young versus old

persons

DIME: extra items are needed (total items: 26)

• No exclusion based on concomitant treatment

with drugs commonly prescribed for old persons

• The post-marketing data collection in geriatric

patients is specified in the Risk Management Plan

• The extent of drug accumulation in old persons
• Information should be available about dosing

instructions

• The convenience of use for older persons

DIME: extra items are needed, especially about safety

• Potential anticholinergic effects
• Potential sedative effects
• Potential orthostatic effects
• Potential effects on the locomotor system
• Potential cardiovascular side effects
• Potential effects on haemostasis
• Important drug-disease interactions

Final item list of the DIME

Information should be available on: ICH E7 Q&A Inclusion of patients >65 years in phase III studies X Inclusion of patients >75 years in phase III studies X For drugs used in diseases not unique for, but present in, old persons: inclusion

• f at least 100 patients >65 years in the phase III studies

X For drugs used in diseases characteristically associated with aging (e.g. Alzheimer's disease): the majority of the clinical database consists of geriatric patients X No exclusion of patients on the basis of an upper age cut-off X No exclusion based on concomitant treatment with drugs commonly prescribed for old persons X The post-marketing data collection in geriatric patients is specified in the Risk Management Plan X

Final item list

PHARMACOKINETICS

Information should be available on: ICH E7 Huisman et al. A multiple-dose pharmacokinetic study in young versus old persons, if there are age-related differences in pharmacokinetics X The extent of drug accumulation in old persons X The extent of renal clearance of the active substances (i.e. parent compound and/

• r metabolites) in old persons

X The extent of hepatic clearance of the active substances (i.e. parent compound and/ or metabolites) in old persons X The therapeutic dose range of the drug X The extent of metabolism via or effects on specified CYP450 enzymes X Potential drug-drug interactions, if the therapeutic range of the drug or likely concomitant drugs is narrow, and the likelihood of the concomitant therapy is great X

Huisman et al. Drugs and Aging 2011; 28: 391-402

Final item list

EFFICACY

Information should be available on: ICH E7 Age-related differences in efficacy X Age-related differences in dose-response X

Final item list

SAFETY

Information should be available on: ICH E7 Huisman et al. Age-related differences in adverse events X Potential anticholinergic effects (e.g. cognitive decline, delirium, blurred vision, urine retention) X Potential sedative effects X Potential orthostatic effects X Potential effects on the locomotor system (e.g. decline of mobility, increased incidence of falls) X Potential cardiovascular side effects (e.g. arrhythmias, ischemic effects) X Potential effects on haemostasis (e.g. thrombotic effects, bleeding risk) X Important drug-disease interactions (e.g. exacerbation of heart failure) X

Final item list

CONVENIENCE OF USE

Information should be available on: Huisman et al. Delphi panel The convenience of use for older persons (dosage form and packaging) X Information should be available about dosing instructions X